CIDP is the most common acquired autoimmune peripheral neuropathy and affects 1 in 10,000 people. Patients suffer from progressive demyelination of peripheral nerves, leading to sensory and motor dysfunction. Current treatments for CIDP are expensive, invasive, have deleterious side effects, and clinical symptoms persist in as many as 70% of patients despite therapy. The cells and cytokines that mediate CIDP are poorly understood, hampering the development of mechanism-based therapies. Our long-term goal is to find specific, mechanism-based therapeutic targets for CIDP by studying Aire-deficient mice that develop spontaneous autoimmune peripheral polyneuropathy (SAPP) resembling CIDP. This proposal will investigate two well- described immunoregulators: 1) regulatory T cells (Tregs) and 2) the cytokine interleukin-10 (IL-10), in the pathogenesis of SAPP. Tregs are potent suppressors of autoreactive T cells in the periphery. CIDP is associated with reductions in Treg numbers and suppressive function. Our data showed that Treg depletion accelerated SAPP in Aire-deficient mice, suggesting Tregs are important for preventing SAPP. Tregs can suppress inflammation by secreting IL-10, a cytokine that potently suppresses inflammation by suppressing the production of pro- inflammatory mediators. Paradoxically, our data showed that IL-10 deficiency protected Aire-deficient mice from SAPP, suggesting IL-10 is pro-inflammatory in SAPP. IL-10 has been shown to perform pro-inflammatory roles in disease. Consistent with a pro-inflammatory phenotype, CIDP patients have increased IFN-?, IL-10, and pSTAT1 in CD4+ T cells and monocytes relative to healthy controls. These data suggest the hypothesis that defective Treg suppressive function and the pro-inflammatory effects of IL-10 contribute to the pathogenesis of SAPP. AIM 1 will determine whether Aire deficiency causes defective Treg suppressive function, and whether these defective Tregs contribute to the pathogenesis of SAPP. Treg functional markers and suppressive function in vitro and in vivo will be measured. AIM 2 will determine the mechanism by which IL-10 is pathogenic in SAPP. Secretors of IL-10 in nerves, the effects of IL-10 deficiency on T cell and macrophage activation and cytokine production, and the immune cell compartment that protects from SAPP in IL-10 deficiency will be determined. Investigation of immunoregulation in CIDP may reveal more efficacious therapeutic targets. The results of this proposal will provide preclinical rationale for Treg and IL-10-blocking therapies in CIDP. The superior clinical and research opportunities at UNC Chapel Hill, exceptional mentoring of Drs. Maureen Su and Roland Tisch, and rigorous training plan in this fellowship will empower my development as a physician-scientist in immunology.